Associations among maternal lifetime trauma, psychological symptoms in pregnancy, and infant stress reactivity and regulation.

Maternal trauma has intergenerational implications, including worse birth outcomes, altered brain morphology, and poorer mental health. Research investigating intergenerational effects of maternal trauma on infant stress reactivity and regulation is limited. Maternal mental health during pregnancy may be a contributor: psychopathology is a sequela of trauma exposure and predictor of altered self-regulatory capacity in offspring of affected mothers. We assessed associations among maternal lifetime trauma and infant stress responsivity, mediated by psychological symptoms in pregnancy. Mothers reported lifetime trauma history and anxiety, depressive, and posttraumatic stress symptoms during pregnancy. At infant age 6 months, stress reactivity and regulation were assessed via maternal behavior ratings (Infant Behavior Questionnaire-Revised, IBQ-R) and behavioral (negative mood) and physiological (respiratory sinus arrhythmia, RSA) markers during a laboratory stressor (Still-Face Paradigm). Maternal trauma was directly associated with lower infant physiological regulation and indirectly associated with lower levels of both infant behavioral and physiological regulation via higher maternal anxiety during pregnancy. Maternal trauma was also indirectly associated with higher infant reactivity via higher maternal anxiety during pregnancy. Post hoc analyses indicated differential contributions of maternal prenatal versus postnatal anxiety to infant outcomes. Findings highlight potential contributory mechanisms toward maladaptive child stress response, which has been associated with poor behavioral, cognitive, and academic outcomes.

Effects of Maternal and Child Lifetime Traumatic Stress Exposures, Infant Temperament, and Caregiving Quality on Preschoolers' Executive Functioning.

We examined effects of maternal and child lifetime traumatic stress exposures, infant temperament, and caregiving quality on parent ratings of preschoolers' executive functioning (EF). Maternal lifetime trauma was associated with preschoolers' EF problems; this association was mediated by greater child trauma exposure. Infant temperament was associated with EF abilities, particularly among females. Among males, infant extraversion/surgency mediated the association of maternal lifetime trauma with poorer child EF. Caregiving quality was negatively associated with maternal and child trauma exposures but did not predict child EF. Findings have implications for interventions to identify children at risk for poor EF and optimize outcomes.

Functional abdominal pain symptom severity: Associations between cognition and emotion in a pediatric sample.

Functional abdominal pain (FAP) is a common physical complaint in children and adolescents. Prior research has documented associations between FAP symptoms and mood, especially internalizing behaviors. Limited research is available examining the association between symptom burden and cognitive function in this pediatric population. This study explored associations between FAP symptoms, internalizing behaviors, and cognitive and school function in children and adolescents. Twenty-seven participants (mean age = 12.6 years, range 8.8-16.5; 33% male) diagnosed with FAP completed assessments of cognitive, emotional, and behavioral function, as well as FAP symptom severity. Mean performances on cognitive tests were within age-expected ranges. Within this context, however, higher overall burden of FAP symptoms was associated with slower processing speed, more self-reported metacognitive problems and internalizing behaviors, and more school absences. Cognitive function was systematically associated with internalizing behaviors but not physical symptoms. Overall, findings revealed that FAP may be associated with cognitive inefficiencies in addition to internalizing problems. Cognitive symptoms may be linked to internalizing behaviors associated with FAP.

Special Education Services and School-Related Quality of Life in Children With Learning Disorders and Their Families: A One-Year Follow-Up Study.

Learning disorders can have adverse impacts on children and families extending beyond the academic skills deficits. The goal of the present study was to assess the impact of the school's response, following an independent evaluation, for child and family school-related quality of life (QOL). We hypothesized that a positive school response would be associated with improved QOL. Parents completed the LDQOL/15, a brief measure of school-related QOL, at the time that their child received an independent evaluation and again a year later (N = 155). At follow-up, parents reported the tenor of the school's response to the evaluation and whether special education services had changed. QOL problems were very high in this referred population, with 66% of respondents rating a level of problems in the clinical range at baseline. Predicted interactions between time of assessment (baseline/follow-up) and the school's response to the evaluation were confirmed for all outcome variables; a positive school response was associated with improved QOL. Nevertheless, the overall prevalence of school-related QOL problems remained high a year after the evaluation. These findings indicate that special education interventions can mitigate learning disabilities' impacts, but even with these services, many children with learning disorders and their families continue to be significantly affected.

Performance on the ROCF at 8 Years Predicts Academic Achievement at 16 Years in Individuals with Dextro-Transposition of the Great Arteries.

OBJECTIVE: This study examined longitudinal associations between performance on the Rey-Osterrieth Complex Figure-Developmental Scoring System (ROCF-DSS) at 8 years of age and academic outcomes at 16 years of age in 133 children with dextro-transposition of the great arteries (d-TGA). METHOD: The ROCF-DSS was administered at the age of 8 and the Wechsler Individual Achievement Test, First and Second Edition (WIAT/WIAT-II) at the ages of 8 and 16, respectively. ROCF-DSS protocols were classified by Organization (Organized/Disorganized) and Style (Part-oriented/Holistic). Two-way univariate (ROCF-DSS Organization × Style) ANCOVAs were computed with 16-year academic outcomes as the dependent variables and socioeconomic status (SES) as the covariate. RESULTS: The Organization × Style interaction was not statistically significant. However, ROCF-DSS Organization at 8 years was significantly associated with Reading, Math, Associative, and Assembled academic skills at 16 years, with better organization predicting better academic performance. CONCLUSIONS: Performance on the ROCF-DSS, a complex visual-spatial problem-solving task, in children with d-TGA can forecast academic performance in both reading and mathematics nearly a decade later. These findings may have implications for identifying risk in children with other medical and neurodevelopmental disorders affecting brain development.

Developmental Dyspraxia in Children With Learning Disorders: Four-Year Experience in a Referred Sample.

OBJECTIVE: The term apraxia is clearly understood in adult behavioral neurology, with assessment of gesture central to the diagnosis. In contrast, the concept of "developmental dyspraxia" has been more problematic. In an effort to better specify its potential significance, we describe preliminary practice-based evidence for understanding developmental dyspraxia acquired within a theoretical framework informed by both adult behavioral neurology and a neuroconstructivist appreciation of neurodevelopmental disorders. Specifically, we describe the experience of a diagnostic clinic for children with learning disorders that adopted this framework and compare clinical characteristics of children diagnosed with dyspraxia with those of children diagnosed with dyslexia during the same time period. METHOD: The dyspraxia diagnosis was based on the presence of impaired gesture and/or cognitive problems with planning. Over the target period, 71 children were diagnosed with dyspraxia and 114 children were diagnosed with dyslexia. Twenty-nine of the 71 children with dyspraxia were also diagnosed with dyslexia. Domains assessed included early developmental milestones, neurologic findings, cognition, speech and language, academic skills, and psychosocial functioning. RESULTS: Compared to the dyslexia group, children with dyspraxia (with or without dyslexia) had more problems with speech and language planning and planning in everyday life. Children with dyspraxia without dyslexia had more frequent early motor delays and deficits in visuospatial production than the other groups. The dyslexia groups predictably demonstrated poorer single word reading and phonologic processing compared to the dyspraxia only group (all P < .01). CONCLUSIONS: A neurologic finding of impaired gesture in children with learning disorders may signal a broader neurodevelopmental profile of developmental dyspraxia with both theoretical relevance and meaningful implications for evaluation and treatment. Cognitive problems with planning are particularly relevant.

Consensus Parameter: Research Methodologies to Evaluate Neurodevelopmental Effects of Pubertal Suppression in Transgender Youth.

Purpose: Pubertal suppression is standard of care for early pubertal transgender youth to prevent the development of undesired and distressing secondary sex characteristics incongruent with gender identity. Preliminary evidence suggests pubertal suppression improves mental health functioning. Given the widespread changes in brain and cognition that occur during puberty, a critical question is whether this treatment impacts neurodevelopment. Methods: A Delphi consensus procedure engaged 24 international experts in neurodevelopment, gender development, puberty/adolescence, neuroendocrinology, and statistics/psychometrics to identify priority research methodologies to address the empirical question: is pubertal suppression treatment associated with real-world neurocognitive sequelae? Recommended study approaches reaching 80% consensus were included in the consensus parameter. Results: The Delphi procedure identified 160 initial expert recommendations, 44 of which ultimately achieved consensus. Consensus study design elements include the following: a minimum of three measurement time points, pubertal staging at baseline, statistical modeling of sex in analyses, use of analytic approaches that account for heterogeneity, and use of multiple comparison groups to minimize the limitations of any one group. Consensus study comparison groups include untreated transgender youth matched on pubertal stage, cisgender (i.e., gender congruent) youth matched on pubertal stage, and an independent sample from a large-scale youth development database. The consensus domains for assessment includes: mental health, executive function/cognitive control, and social awareness/functioning. Conclusion: An international interdisciplinary team of experts achieved consensus around primary methods and domains for assessing neurodevelopmental effects (i.e., benefits and/or difficulties) of pubertal suppression treatment in transgender youth.

Detecting microstructural white matter abnormalities of frontal pathways in children with ADHD using advanced diffusion models.

Studies using diffusion tensor imaging (DTI) have documented alterations in the attention and executive system in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). While abnormalities in the frontal lobe have also been reported, the associated white matter fiber bundles have not been investigated comprehensively due to the complexity in tracing them through fiber crossings. Furthermore, most studies have used a non-specific DTI model to understand white matter abnormalities. We present results from a first study that uses a multi-shell diffusion MRI (dMRI) data set coupled with an advanced multi-fiber tractography algorithm to probe microstructural measures related to axonal/cellular density and volume of fronto-striato-thalamic pathways in children with ADHD (N = 30) and healthy controls (N = 28). Head motion was firstly examined as a priority in order to assure that no group difference existed. We investigated 45 different white matter fiber bundles in the brain. After correcting for multiple comparisons, we found lower axonal/cellular packing density and volume in ADHD children in 8 of the 45 fiber bundles, primarily in the right hemisphere as follows: 1) Superior longitudinal fasciculus-II (SLF-II) (right), 2) Thalamus to precentral gyrus (right), 3) Thalamus to superior-frontal gyrus (right), 4) Caudate to medial orbitofrontal gyrus (right), 5) Caudate to precentral gyrus (right), 6) Thalamus to paracentral gyrus (left), 7) Caudate to caudal middlefrontal gyrus (left), and 8) Cingulum (bilateral). Our results demonstrate reduced axonal/cellular density and volume in certain frontal lobe white matter fiber tracts, which sub-serve the attention function and executive control systems. Further, our work shows specific microstructural abnormalities in the striato-thalamo-cortical connections, which have not been previously reported in children with ADHD.

Quality of Life in Children and Adolescents With Learning Problems: Development and Validation of the LD/QOL15 Scale.

Learning problems (LP) can have wider implications than the academic deficits per se. The goal of the present series of studies was to develop a reliable and valid quality-of-life measure targeted to children and adolescents with LP. In Study 1, using a 35-item questionnaire, we surveyed 151 parents/guardians of children referred for assessment of learning disorders. Exploratory factor analysis identified a three-factor model: Academic Performance, School Understanding, and Child/Family Psychological. These factors were validated against standardized measures of academic achievement and psychosocial functioning. The questionnaire was then reduced to 15 items-the LD/QOL15 -and administered to a community sample of 325 parents/guardians of children in Grades 1 to 8 (Study 2). The three-factor model was verified with confirmatory factor analysis. Comparison of general education ( n = 232) and LP ( n = 93) groups within the community sample documented substantial group differences ( p < .0001), with the LP group having higher mean scores. These differences were larger for older students (Grades 5-8) than younger students (Grades 1-4; p < .01). The LD/QOL15 is a brief and reliable measure that is valid to assess quality of life and, potentially, outcomes in children and adolescents with LP.

Self-reported visual symptoms in children with developmental dyslexia.

Although there are many anecdotal reports of children with developmental dyslexia complaining of vision symptoms when reading, empirical studies are lacking. The primary aim of the present study was to document self-reported vision-related symptoms in children with developmental dyslexia and typically reading peers. We also explored whether vision symptoms were correlated with sensorimotor measures of vergence, accommodation and ocular motor tracking skills. Using a prospective group comparison observational design, we assessed 28 children with developmental dyslexia (DD) and 33 typically reading children (TR) 7-11 years of age. Participants completed psychoeducational testing, a comprehensive sensorimotor eye examination, and the Convergence Insufficiency Symptom Survey (CISS), which includes 9 items pertaining to vision-related symptoms (CISS-V) and 6 that could have cognitive influence (CISS-C). CISS-V were significantly greater in DD than TR children. Ocular motor tracking, assessed by an infra-red limbal eye tracker while reading text, was most clearly associated with the visual symptoms, but only within the DD group. Vision-related symptom surveys followed by a comprehensive eye examination with detailed evaluation of sensorimotor functioning for those who report a high prevalence of symptoms may be clinically relevant for children with DD.

Frequency of Visual Deficits in Children With Developmental Dyslexia.

Importance: Developmental dyslexia (DD) is a specific learning disability of neurobiological origin whose core cognitive deficit is widely believed to involve language (phonological) processing. Although reading is also a visual task, the potential role of vision in DD has been controversial, and little is known about the integrity of visual function in individuals with DD. Objective: To assess the frequency of visual deficits (specifically vergence, accommodation, and ocular motor tracking) in children with DD compared with a control group of typically developing readers. Design, Setting, and Participants: A prospective, uncontrolled observational study was conducted from May 28 to October 17, 2016, in an outpatient ophthalmology ambulatory clinic among 29 children with DD and 33 typically developing (TD) children. Main Outcomes and Measures: Primary outcomes were frequencies of deficits in vergence (amplitude, fusional ranges, and facility), accommodation (amplitude, facility, and accuracy), and ocular motor tracking (Developmental Eye Movement test and Visagraph eye tracker). Results: Among the children with DD (10 girls and 19 boys; mean [SD] age, 10.3 [1.2] years) and the TD group (21 girls and 12 boys; mean [SD] age, 9.4 [1.4] years), accommodation deficits were more frequent in the DD group than the TD group (16 [55%] vs 3 [9%]; difference = 46%; 95% CI, 25%-67%; P < .001). For ocular motor tracking, 18 children in the DD group (62%) had scores in the impaired range (in the Developmental Eye Movement test, Visagraph, or both) vs 5 children in the TD group (15%) (difference, 47%; 95% CI, 25%-69%; P < .001). Vergence deficits occurred in 10 children in the DD group (34%) and 5 children in the TD group (15%) (difference, 19%; 95% CI, -2.2% to 41%; P = .08). In all, 23 children in the DD group (79%) and 11 children in the TD group (33%) had deficits in 1 or more domain of visual function (difference, 46%; 95% CI, 23%-69%; P < .001). Conclusions and Relevance: These findings suggest that deficits in visual function are far more prevalent in school-aged children with DD than in TD readers, but the possible cause and clinical relevance of these deficits are uncertain. Further study is needed to determine the extent to which treating these deficits can improve visual symptoms and/or reading parameters.

Parental history of moderate to severe infantile malnutrition is associated with cognitive deficits in their adult offspring.

OBJECTIVES: We compared the IQ and academic achievement of the young adult offspring of parents malnourished in infancy and those of a healthy control group in order to test the hypothesis that the offspring of previously malnourished individuals would show IQ and academic deficits that could be related to reduced parental socioeconomic status. METHODS: We conducted a group comparison study based on a community sample in Barbados (Barbados Nutrition Study). Participants were adult children ≥16 years of age whose parents had been malnourished during the first year of life (n = 64; Mean age 19.3 years; 42% male) or whose parents were healthy community controls (n = 50; Mean age 19.7 years; 48% male). The primary outcome was estimated IQ (Wechsler Abbreviated Scale of Intelligence); a secondary outcome was academic achievement (Wide Range Achievement Test - Third Edition). Data were analyzed using PROC MIXED with and without adjusting for parental socioeconomic status (Hollingshead Index of Social Position). RESULTS: IQ was reduced in the offspring of previously malnourished parents relative to the offspring of controls (9.8 point deficit; P < 0.01), but this difference was not explained by parental socioeconomic status or parental IQ. The magnitude of the group difference was smaller for basic academic skills and did not meet criteria for statistical significance. DISCUSSION: The deleterious impact of infant malnutrition on cognitive function may be transmitted to the next generation; however, this intergenerational effect does not appear to be explained by the reduced socioeconomic status or IQ of the parent generation.

Relationship between infant malnutrition and childhood maltreatment in a Barbados lifespan cohort.

Childhood malnutrition and maltreatment (abuse, neglect) are both prevalent, particularly in resource-limited settings. Despite their known negative impact on child development, there is surprisingly little research documenting their interrelationships. To address this gap, we administered the Childhood Trauma Questionnaire-Short Form (CTQ-SF), a retrospective structured self-report of childhood abuse and neglect, in a Barbadian cohort of 77 adult survivors of infant malnutrition, limited to the first year of life, and 62 healthy controls from the same classrooms and neighborhoods (mean age ± SD = 43.8±2.3 years). This cohort has been followed since birth. Using factor analysis and comparison with archival data addressing similar constructs, we found evidence for reliability and validity of the CTQ-SF in this population. Linear regression analyses, with and without adjusting for childhood household standard of living at three childhood ages, revealed that a history of infant malnutrition was significantly associated with increased levels of self-reported physical neglect in childhood, and, to a somewhat lesser degree, emotional neglect. This study highlights the co-occurrence of infant malnutrition and self-reported maltreatment in childhood in Barbados, with potential public health implications.

Ascertaining educational outcomes after assessment in children with learning disorders.

OBJECTIVE: To survey educational outcomes after an interdisciplinary, neuropsychologically based team assessment for learning disorders. METHOD: Parents of 137 children who underwent a comprehensive interdisciplinary neuropsychologically based assessment for learning problems completed an online survey one to four years later. Questions pertained broadly to school outcomes: positive or negative school responses, changes in special education services, and parental perceptions about the helpfulness of those services. These outcomes were examined in relation to demographic characteristics and parent satisfaction with the evaluation. We also obtained recent performance on state-based academic testing for descriptive purposes. RESULTS: Parents reported that schools generally responded positively (78%), and 70% reported that their children had access to more or different special education services after the evaluation. Parents nearly uniformly (98%) viewed these services as helpful. Positive changes in education services were related to income (lower income received more services, p < .05) and parent satisfaction with the evaluation (p < .05). The intensity of special education services was strongly related to performance on state-based testing (p < .0001-p < .01). CONCLUSIONS: School response is a relatively objective and meaningful metric of educational outcome after neuropsychologically based evaluation for children with learning problems.

DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition.

BACKGROUND: Early childhood malnutrition affects 113 million children worldwide, impacting health and increasing vulnerability for cognitive and behavioral disorders later in life. Molecular signatures after childhood malnutrition, including the potential for intergenerational transmission, remain unexplored. METHODS: We surveyed blood DNA methylomes (~483,000 individual CpG sites) in 168 subjects across two generations, including 50 generation 1 individuals hospitalized during the first year of life for moderate to severe protein-energy malnutrition, then followed up to 48 years in the Barbados Nutrition Study. Attention deficits and cognitive performance were evaluated with the Connors Adult Attention Rating Scale and Wechsler Abbreviated Scale of Intelligence. Expression of nutrition-sensitive genes was explored by quantitative reverse transcriptase polymerase chain reaction in rat prefrontal cortex. RESULTS: We identified 134 nutrition-sensitive, differentially methylated genomic regions, with most (87%) specific for generation 1. Multiple neuropsychiatric risk genes, including COMT, IFNG, MIR200B, SYNGAP1, and VIPR2 showed associations of specific methyl-CpGs with attention and IQ. IFNG expression was decreased in prefrontal cortex of rats showing attention deficits after developmental malnutrition. CONCLUSIONS: Early childhood malnutrition entails long-lasting epigenetic signatures associated with liability for attention and cognition, and limited potential for intergenerational transmission.

Polymorphisms in Genes Related to Oxidative Stress Are Associated With Inferior Cognitive Function After Therapy for Childhood Acute Lymphoblastic Leukemia.

PURPOSE: Survivors of childhood acute lymphoblastic leukemia (ALL) exhibit increased rates of neurocognitive deficits. This study was conducted to test whether interpatient variability in neurocognitive outcomes can be explained by polymorphisms in candidate genes conferring susceptibility to neurocognitive decline. METHODS: Neurocognitive testing was conducted in 350 pediatric leukemia survivors, treated on Dana-Farber Cancer Institute ALL Consortium Protocols 95-01 or 00-01. Genomic DNA was isolated from bone marrow collected at remission. Candidate polymorphisms were selected on the basis of prior literature, targeting genes related to drug metabolism, oxidative damage, altered neurotransmission, neuroinflammation, and folate physiology. Single nucleotide polymorphisms were detected using either a customized multiplexed Sequenom MassARRAY assay or polymerase chain reaction-based allelic discrimination assays. Multivariable logistic regression models were used to estimate the effects of genotype on neurocognitive outcomes, adjusted for the effects of demographic and treatment variables. False-discovery rate correction was made for multiple hypothesis testing, indicated as a Q value. RESULTS: Inferior cognitive or behavioral outcomes were associated with polymorphisms in three genes related to oxidative stress and/or neuroinflammation: NOS3 (IQ, Q = 0.008; Vocabulary Q = 0.011; Matrix Reasoning Q = 0.008), SLCO2A1 (IQ Q = 0.043; Digit Span Q = 0.006; Block Design Q = 0.076), and COMT (Behavioral Assessment System for Children-2 Attention Q = 0.080; and Hyperactivity Q = 0.084). Survivors homozygous for NOS3 894T, with at least one SLCO2A1 variant G allele or with at least one GSTP1 variant allele, had lower mean estimated IQ scores than those without these genotypes. CONCLUSION: These data are consistent with the hypothesis that oxidative damage contributes to chemotherapy-associated neurocognitive decline among children with leukemia.

Lexical retrieval pre- and posttemporal lobe epilepsy surgery in a pediatric sample.

PURPOSE: This study aimed to evaluate lexical retrieval, presurgery and postsurgery, among children and adolescents who had undergone temporal lobe resection for intractable epilepsy and to compare outcomes in patients whose surgery involved the left temporal lobe or the right temporal lobe. MATERIALS AND METHODS: A retrospective chart review identified 36 patients from a major pediatric epilepsy treatment center who had undergone temporal lobe resection (21 underwent left temporal lobe resection; 15 underwent right temporal lobe resection) for intractable epilepsy and who had completed neuropsychological testing that included a measure of confrontation naming (Boston Naming Test, BNT) and verbal fluency (Delis-Kaplan Executive Function System (D-KEFS) Fluency) prior to and after surgery. Linear mixed effects regression models were used to evaluate presurgery and postsurgery changes and to compare the left temporal lobe resection group with the right temporal lobe resection group. PRINCIPAL RESULTS: Confrontation naming performance declined after left, but not right, temporal lobe resection (p<0.05). This effect was not documented for verbal fluency. MAJOR CONCLUSIONS: Left temporal lobe resection for intractable epilepsy is associated with a decline in lexical retrieval. The risk of decline in specific language functions following surgery involving the left temporal lobe should be incorporated in the counseling of patients and families in decision-making with regard to surgery.

Neuroanatomical correlates of behavioral rating versus performance measures of working memory in typically developing children and adolescents.

OBJECTIVE: The frequent lack of correspondence between performance and observational measures of executive functioning, including working memory, has raised questions about the validity of the observational measures. This study was conducted to investigate sources of this discrepancy through correlation of volumetric and cortical thickness (CT) neuroimaging values with performance and questionnaire measures of working memory (WM). METHODS: Using longitudinal data from the NIH MRI Study of Normal Brain Development (Volumes, N= 347, 54.3% female; CT, N= 350, 54.6% female; age range: 6 to 16.9 years), scores on the Behavioral Rating Inventory of Executive Function (BRIEF) WM, Emotional Control (EC) and Inhibition (INH) scales; Wechsler Scale of Intelligence for Children-III Digit Span; and Cambridge Neuropsychological Test Battery Spatial Working Memory (CANTAB SWM) were correlated with each other and with morphometric measurements using mixed effects linear regression models. RESULTS: BRIEF WM was correlated with CANTAB SWM (p < .001). With whole brain correction, BRIEF WM and EC were both correlated with CT of the posterior parahippocampal gyrus (PHG), EC on the right side only. Performance measures of WM were unrelated to lobar volumes or CT, but were associated with volumes of hippocampus and amygdala. CONCLUSIONS: The known role of PHG in contextual learning suggests that the BRIEF WM assesses contextualized learning/memory, potentially explaining its loose correspondence to the decontextualized performance measures. Observational measures can be useful and valid functional metrics, complementing performance measures. Labels used to characterize scales should be interpreted with caution, however.